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  3. Lipid Peroxidation Products 4-ONE and 4-HNE Modulate Voltage-Gated Sodium Channels in Neuronal Cell Lines and DRG Action Potentials

Lipid Peroxidation Products 4-ONE and 4-HNE Modulate Voltage-Gated Sodium Channels in Neuronal Cell Lines and DRG Action Potentials

  • Antioxidants (Basel). 2026 Feb 4;15(2):206. doi: 10.3390/antiox15020206.
Ming-Zhe Yin 1 2,  Na Kyeong Park 2 3,  Mi Seon Seo 4,  Jin Ryeol An 4 5,  Hyun Jong Kim 4 5,  JooHan Woo 4,  Jintae Kim 6,  Min Yan 1,  Sung Joon Kim 2 7,  Seong Woo Choi 4 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 2 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
  • 3 Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Republic of Korea.
  • 4 Department of Physiology, College of Medicine, Dongguk University, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea.
  • 5 Channelopathy Research Center (CRC), College of Medicine, Dongguk University, 32 Dongguk-ro, Ilsan Dong-gu, Goyang 10326, Republic of Korea.
  • 6 Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Wangsimni-ro 222, Seongdong-gu, Seoul 04763, Republic of Korea.
  • 7 Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
PMID: 41750587 DOI: 10.3390/antiox15020206
Abstract

Oxidative stress-induced lipid peroxidation products (LPPs), particularly 4-hydroxy-nonenal (4-HNE) and 4-oxo-nonenal (4-ONE), have recently gained attention for their direct regulation of ion channels essential for pain signaling. In this study, we investigated how these two LPPs affect the electrophysiological properties of neurons, specifically voltage-gated sodium (NaV) channels, thereby influencing sensory neuron excitability and pain pathways. Using human neuroblastoma (SH-SY5Y) and ND7/23 cells (a fusion cell line exhibiting partial sensory neuron properties), we measured changes in NaV channel-mediated sodium currents following treatment with 4-HNE or 4-ONE. Whole-cell patch-clamp experiments showed that 4-ONE (10 µM) and 4-HNE (100 µM) did not significantly alter the peak sodium current amplitude in SH-SY5Y cells. However, in ND7/23 cells, both 4-HNE and 4-ONE induced a negative shift in NaV channel activation voltage dependence, enabling Sodium Channel activation at lower membrane potentials. Furthermore, current-clamp recordings in primary mouse dorsal root ganglion neurons demonstrated that treatment with 4-ONE and 4-HNE reduced the current threshold required to elicit action potentials and significantly increased action potential firing frequency. These findings indicate that LPPs enhance pain sensitivity by modulating NaV channels, which play a crucial role in pain transmission. In conclusion, 4-HNE and 4-ONE shift the voltage-dependent activation of sodium channels toward more negative potentials, thereby increasing the excitability of primary sensory neurons and amplifying pain signals. This study provides molecular insights into how oxidative stress-related lipid peroxidation contributes to sensory mechanisms and offers potential avenues for developing new treatments for oxidative stress- or inflammation-associated pain.

Keywords

4-hydroxy-nonenal; 4-oxo-nonenal; dorsal root ganglion; voltage-gated sodium channels.

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